The ovarian/menstrual cycle is a complex process characterized by an estrogen rich follicular phase and, after ovulation, a progesterone rich luteal phase. Luteal phase has a duration of approximately 14 days resulting while the duration of the follicular phase may vary considerably resulting in an intermenstrual interval of 20 to more than 45 days. Habitual cycle length in the majority of women however varies from 25 to 34 days.
The onset of menstruation is generally considered to be the beginning of a new menstrual cycle and is generally counted as Day 1.
After each menses, the ovaries are stimulated by follicle stimulating hormone (FSH) released by the pituitary to grow a cohort of growing follicles. These follicles each comprise an oocyte (egg cell) which is enveloped by an orb of granulosa cells. During growth of the follicles several layers of granulosa cells are being formed. Follicle maturation during the normal menstrual cycle occurs in 12-14 days. Gradually, one follicle becomes dominant and the others become atretic. Maturation of the dominant follicle usually takes 5-7 days. As the number of granulosa cells increases more estrogen is secreted by these cells.
Once the dominant follicle has reached maturity, the follicle will burst (ovulate) under the action of a surge of luteinising hormone (LH) which is released by the pituitary in response to the increased blood serum estrogen level (positive feedback). The oocyte is discharged from the follicle into the ampulla of the Fallopian tube, where fertilization may take place. The oocyte or embryo is transported to the uterus in 5-7 days, where implantation may occur in the midluteal phase.
The follicle that has discharged the oocyte is transformed into a new hormone producing organ, the corpus luteum. The corpus luteum produces amongst others progesterone and estrogens. The corpus luteum has a limited lifespan of about 12-14 days, unless pregnancy occurs. During the second part of that period, it ceases functioning, and as a result the blood level of estrogens and progesterone drops. The decline of progesterone causes shedding of the lining of the uterus and thus menstruation.
In particular in the area of ovulation induction, the past decades have shown the development and commercial introduction of numerous drugs assisting in fertility management of infertile couples. Amongst others, these include anti-estrogens (like clomiphene citrate and tamoxifen citrate), pulsatile gonadotropin releasing hormone (GnRH), purified and recombinant gonadotropins, and GnRH agonists and antagonists. The specific drugs used and administration regimens chosen largely depend on the goal of the treatment, e.g. the induction of mono-ovulation in anovulatory females or the controlled ovarian hyperstimulation to induce multiple follicular development as an element in assisted reproductive technologies (ART).
Even when the couple does not suffer from any disorder which may affect their fertility, the woman may confront difficulties to get pregnant. The fertile window is very short and generally lasts five days, typically from four days before ovulation to the day of ovulation (included). The ovulation date varies from menstrual cycle to menstrual cycle for the same woman, as the length of the menstrual cycle also varies. It may thus be very difficult for a woman to predict the occurrence of the ovulation and thus to schedule fertilizing intercourses. Thus, there is still a need for a safe drug that would not only induce but, most importantly, also control the timing of ovulation.
Indeed scheduling the event of ovulation, for example in females who suffer from ovulation dysregulation, irregular menstrual cycle, would be very helpful for improving infertility management.